Department of Medicinal and Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Girls Branch, Cairo, Egypt.
Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, 41522, Egypt.
Eur J Med Chem. 2021 Oct 15;222:113609. doi: 10.1016/j.ejmech.2021.113609. Epub 2021 Jun 5.
This work presents the design and synthesis of a series of new quinazolin-4-one derivatives, based on the established effectiveness of quinazoline-based small molecules as anticancer agents. Synthesized compounds were more potent against MCF-7 than A-549 with low to submicromolar ICs. Compound 17 exhibited the best IC being equipotent with the positive control doxorubicin (IC 0.06 μM) and better than 5-fluorouracil (IC 2.13 μM). Compound 17 was further tested against MDA-MB-231 and MCF-10A and was found to be > 2 folds more cytotoxic on MCF-7. Significant apoptotic activity was elicited by 17 on MCF-7 where it increased apoptotic cell death along with induction of pre-G1 and G1-phase cell cycle arrest. Similarly, 17 was able to induce apoptosis in MD-MB-231 treated cells associated with a disruption of the cell cycle causing arrest at the pre-G1 and S phases. Investigation of gene expression in MCF-7 demonstrated an increased expression of the proapoptotic genes P53, PUMA, Bax, caspases 3, 8 and 9 and a decrease of the anti-apoptotic gene Bcl2. Also, 17 reduced autophagy giving way for apoptosis to induce cancer cells death. This latter observation was associated with downregulation of EGFR and its downstream effectors PI3K, AKT and mTor. As its biomolecular target, 17 also inhibited EGFR similar to erlotinib (IC = 0.072 and 0.087 μM, respectively). Additionally, in vivo testing in a mouse model of breast cancer affirmed the anti-tumor efficacy of 17. Finally, docking of 17 against EGFR ATP binding site demonstrated its ability to bind with EGFR resembling erlotinib.
本工作基于喹唑啉类小分子作为抗癌剂的有效性，设计并合成了一系列新型喹唑啉-4-酮衍生物。合成的化合物对 MCF-7 的活性高于 A-549，IC 低至亚微摩尔。化合物 17 的 IC 与阳性对照阿霉素（IC 0.06 μM）相当，优于 5-氟尿嘧啶（IC 2.13 μM），对 MCF-7 的抑制作用最强。化合物 17 进一步在 MDA-MB-231 和 MCF-10A 中进行了测试，发现对 MCF-7 的细胞毒性增加了> 2 倍。17 在 MCF-7 中引起了明显的凋亡活性，它增加了凋亡细胞死亡，同时诱导了预 G1 和 G1 期细胞周期阻滞。同样，17 能够诱导 MD-MB-231 处理的细胞凋亡，导致细胞周期阻滞在预 G1 和 S 期。在 MCF-7 中对基因表达的研究表明，促凋亡基因 P53、PUMA、Bax、caspase 3、8 和 9 的表达增加，抗凋亡基因 Bcl2 的表达减少。此外，17 减少了自噬，使细胞凋亡诱导癌细胞死亡。这一观察结果与 EGFR 及其下游效应物 PI3K、AKT 和 mTor 的下调有关。作为其生物分子靶标，17 对 EGFR 的抑制作用与厄洛替尼相似（IC 分别为 0.072 和 0.087 μM）。此外，在乳腺癌小鼠模型中的体内试验证实了 17 的抗肿瘤疗效。最后，17 与 EGFR ATP 结合位点的对接表明，它能够与 EGFR 结合，类似于厄洛替尼。
